Frontotemporal lobar degeneration (FTLD) accounts for 10-20% of dementia cases in individuals under age 65, and is a fatal disease with no available treatments. Three single nucleotide polymorphisms (SNPs) at the TMEM106B locus have been associated with increased risk of FTLD-TDP, the most common neuropathological subtype of FTLD, by genome-wide association study (GWAS). The risk allele of the top GWAS SNP, rs1990622, has been associated with increased TMEM106B levels in patient brain and lymphoblastoid cell lines (LCLs), suggesting that risk allele carriers may be more susceptible to disease due to increased TMEM106B expression in one or more brain cell types. TMEM106B levels are also increased in FTLD-TDP brains compared to neurologically normal controls, further establishing the importance of TMEM106B expression in disease. Intriguingly, TMEM106B genotype and expression have also been linked to progranulin, an important secreted neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial FTLD-TDP, and overexpression of TMEM106B in cell culture systems affects intra- and extracellular levels of progranulin. Furthermore, individuals with the risk allee of the TMEM106B SNP rs1990622 have decreased plasma progranulin levels. Therefore, the risk allele of TMEM106B may influence risk for disease through an effect of TMEM106B expression levels on progranulin. The goal of this proposal is to identify the precise molecular mechanisms responsible for the increased TMEM106B levels seen in risk allele carriers, in order to identify regulatory pathways that can be targeted to modulate TMEM106B levels. Based on the linkage disequilibrium structure at the TMEM106B locus and fine-mapping of the LCL eQTL signal, candidate genetic variants were prioritized based on likelihood of regulatory function as assessed by ENCODE experimental data. This comprehensive, unbiased prioritization of variants resulted in the identification of two top candidate SNPs located in a predicted insulator region, which displays haplotype-dependent enhancer-blocking activity in cell-based reporter construct assays. Two major aims based on this preliminary data are proposed: 1) Determine the role of this region in the regulation of TMEM106B by in vivo genome editing, and 2) Identify the SNP(s) responsible for the haplotype effect on insulator function, and the molecular mechanisms involved. Elucidation of the precise molecular mechanisms underlying the association of TMEM106B genotype with expression levels, and by extension, disease risk, will reveal upstream regulatory pathways that can be targeted to manipulate TMEM106B levels.